Vantage Snippets are short summaries of breaking news stories.
With results of INS1007’s Willow study in non-cystic fibrosis bronchiectasis under its belt Insmed put on 41% yesterday, its $2.6bn valuation reflecting the fact that it might no longer be reliant solely on the marketed antibiotic Arikayce. However, close reading of the data throws up a red flag: only the lower of two INS1007 doses was efficacious, something that hints at the finding being due to luck. Willow’s primary endpoint, time to first pulmonary exacerbation at 24 weeks, was just about met by both the 10mg and 25mg doses, though Insmed does not reveal whether the analysis was sequential and whether some subjects were excluded. But rate of pulmonary exacerbations, a secondary measure, was at least as important since this will likely be the primary endpoint of a pivotal trial, and here only 10mg yielded a p value below 0.05. Nevertheless, even though 25mg was not significant, its reduction versus placebo beat a previously defined 20% threshold for proceeding to phase III; moreover, Willow did not show the epidermal desquamation toxicity that had derailed a similar Glaxosmithkline project. Stifel analysts put the lack of dose response down to patient heterogeneity, and said INS1007 could generate blockbuster sales by 2029.
|Summary of Insmed's Willow trial (n=256)|
10mg once daily
25mg once daily
|Time to first pulmonary exacerbation vs placebo (24wk)*||Not disclosed||Not disclosed||NA|
|Rate of pulmonary exacerbations vs placebo (24wk)||36%||25%||NA|
|Rate of adverse events leading to discontinuation||10.6%||7.4%||6.70%|
|Source: company press release; *primary endpoint.|
Blink and you will have missed the significance of Bristol-Myers Squibb’s decision to pull its EU filing for Opdivo plus Yervoy in first-line lung cancer. The move, revealed after market close on Friday, on the face of it looks like a predictable acknowledgement of the uselessness of analysing the combo’s Checkmate-227 study based on patients’ tumour mutation burden; similar considerations saw a US submission pulled a year ago. Not so: Bristol quietly revealed that it had added to the EU filing data from Checkmate-227’s original part 1a – but the EMA rejected this, citing the study’s “multiple protocol changes”. Apparently the US FDA has no such qualms, given that it has agreed to review Opdivo/Yervoy based on a pooled result of part 1 of the study, an even shakier exploratory dataset than part 1a. Yet again the US FDA seems to be behaving more leniently than its EU opposite number. Those who still rate Bristol’s EU chances might have another hope: the company has vowed to file on the basis of Checkmate-9LA, which yielded a survival benefit favouring Opdivo plus Yervoy last October (Bristol might play a role in front-line lung cancer after all, October 23, 2019).
|The Checkmate-227 timeline|
|(Initial study design)
||Part 1a: O+Y or O mono, vs chemo, in PD-L1+ve|
|Part 1b: O+Y or O+chemo, vs chemo, in PD-L1-ve|
|Part 2: O+chemo, vs chemo, in all comers|
|Feb 2018||Bristol claims PFS win in TMB-high patients on O+Y from part 1 combined|
|May 2018||EMA accepts filing in TMB-high patients|
|Jun 2018||US FDA accepts filing in TMB-high patients; Feb 2019 action date|
|Mid-2018||EMA requests OS analysis in TMB-low subjects – and this is almost equal to that in TMB-high cohort|
|Oct 2018||US FDA considers OS data in TMB-low subjects, and delays action date to May 2019|
|Jan 2019||Bristol pulls US filing (TMB-high)|
|Jul 2019||Part 2 fails|
|Sep 2019||Exploratory analysis of part 1 in O+Y all comers is numerically positive for OS|
|2019||Part 1a analysis (OS for O+Y in PD-L1 ≥1%) added to EMA filing|
|Jan 2020||FDA accepts part 1-based filng; May 2020 action date|
|Jan 2020||Bristol pulls EMA filing (TMB-high & part 1a)|
|Other 1st-line NSCLC studies due to report|
|Study (sponsor)||Intervention||Population||Primary endpt||Data||Note|
|Javelin Lung 100 (Merck KGaA/ Pfizer)||Bavencio monotherapy vs various chemos||PDL1 +ve||PFS , OS||Jun 2020||Upsized from 420 to 1,095 to 1,224; all-comers PFS used to be sole primary; completion delayed from Apr to Oct 2019, then to Jun 2020|
|Pearl (Astrazeneca)||Imfinzi monotherapy vs various chemos||PD-L1 ≥25%||OS||Jan 2021||Upsized from 440 to 669; PFS used to be co-primary; completion delayed from Jul 2020|
|NCT03631706 (Merck KGaA)||Bintrafusp alfa vs Keytruda||High PD-L1||ORR, PFS||Mar 2022||–|
|NCT03088540 (Sanofi/ Regeneron)||Libtayo vs chemo||PD-L1 ≥50%||PFS , OS||Feb 2023||Upsized from 300 to 700; completion delayed from Nov 2021; no Keytruda in comparator arm|
|Keynote-598 (Merck & Co)||Keytruda + Yervoy, vs Keytruda||PD-L1 ≥50%||PFS , OS||Feb 2023||Completion delayed from Apr 2022|
No sooner said than done – well, almost. Abbott’s Tendyne has become the first minimally invasive mitral valve prosthesis approved in Europe, a week after the company said it would. The valve is a third-choice therapy: it is only to be used in patients for whom surgery or transcatheter mitral repair is not an option. Abbott, of course, also has the leading second-choice product in the hugely successful MitraClip, and is thus way ahead of its rivals in mitral valve disease. It is also in the best position to make a success of the acquisition of a mitral valve developer. As the table below shows, one of these dealmakers has been unable to move its mitral valve past early trials, and another has given up completely. The next prosthesis to gain CE mark will likely be Medtronic’s Intrepid, which is also the only other project to have started a pivotal US trial – and this could report before Abbott’s does. Medtronic spent much more on its acquisition, however, so investors will want Intrepid to outperform Tendyne, despite its later arrival.
|How the mitral valve acquirers have fared|
|Company||Valve||Company acquisition details||Status|
|Abbott Laboratories||Tendyne||Tendyne, $250m, Jul 2015||CE marked Jan 2020. Data from US trial, Summit, expected 2022|
|Abbott Laboratories||Cephea||Cephea Valve Technologies, initial investment Jul 2015, full acquisition Jan 2019, no terms disclosed||First human trial believed to have ended 2019|
|Medtronic||Intrepid||Twelve, $408m, Aug 2015||European trial believed to have ended 2018; data from US trial, Apollo, due 2021|
|Edwards Lifesciences||Evoque||Possibly the same valve obtained through Cardiaq acquisition, $350m, Jul 2015||In early feasibility trials|
|Livanova||Caisson||Caisson Interventional, $72m to acquire the 51% it did not already own, May 2017||Development ended Nov 2019|
|Source: EvaluateMedTech, clinicaltrials.gov & company communications.|
The IL-10 project pegilodecakin at least failed fairly fast for Lilly, though this is where the positives end. Lilly’s $1.6bn acquisition of Armo Biosciences in May 2018, when cytokines were being described as the next big thing, now looks rash, and hopes for this approach to treating cancer have dimmed substantially since then. On its annual results call today the pharma giant revealed that the two remaining pegilodecakin readouts were duds; hopes that the Cypress lung cancer studies might show a signal were low anyway, after the company dialled back expectations after a blow-up in pancreatic cancer. No further trials are expected with the asset, said Dan Skovronsky, Lilly’s chief science officer, adding that the focus was now largely targeted oncology; the company said today that three other immuno-oncology assets had been canned. This all makes sense given Lilly's the $8bn acquisition of Loxo, which so far seems to have been a wiser move: selpercatinib is likely to receive approval later this year, and the sellside is forecasting sales of $820m by 2024, according to EvaluatePharma. Still, Lilly is far from the only big developer fishing in this pond, and any future moves will not come cheap.
|Out the door|
|Pegilodecakin||IL-10 receptor agonist||II||Cancer|
|Galunisertib||TGF beta R1 kinase inhibitor||II||Cancer|
|Source: company presentation.|
Roche would probably rather not mention its $725m takeover of Seragon, but it is nevertheless keeping the faith in the target company’s chosen mechanism of action, selective oestrogen receptor degraders (SERDs). In its fourth-quarter presentation today the Swiss firm revealed that it was putting a third-generation SERD, coded RG6171, into a phase III breast cancer study, in first-line ER-positive, Her2-negative disease. Just last November Sanofi had highlighted its work in this area, which has yielded the phase II asset SAR439859, but Roche now looks to have leapfrogged its rival. The mechanism is based on degrading or breaking down oestrogen receptors rather than merely blocking them, thus making it relevant in ER-positive breast cancer, whose growth is driven by these receptors. Seragon had brought with it two SERDs, RG6046 and RG6047, but both were discontinued a few years after the takeover (Pre-Esmo jitters for Roche, October 17, 2018).
|SERDs in clinical development for ER+ve/Her2-ve breast cancer|
|SAR439859||Sanofi||Study vs letrozole in preoperative, postmenopausal disease|
|AZD9833||Astrazeneca||Serena-2 study vs fulvestrant|
|Rintodestrant||G1 Therapeutics||Study in advanced disease|
|SHR9549||Jiangsu Hengrui Medicine||Study in advanced disease|
|LSZ102||Novartis||Single-agent or various combos|
|AZD9496||Astrazeneca||Study vs fulvestrant completed|
|Source: EvaluatePharma & clinicaltrials.gov.|
One of the most surprising nuggets of information in Novartis’s full-year financials today was the revelation that its Sandoz division had canned development of a generic version of Glaxosmithkline’s Advair. The Swiss group had widely been expected to refile imminently, having carried out additional work in response to a US complete response letter. But today is said it could no longer see a pathway to launch in the next 18 months, adding that the decision was “data-driven” rather than regulatory. On the face of it this is good news for Hikma/Vectura, whose rival generic has also been derailed by a CRL, though more realistically it underlines just how tough it will be for anyone to get an approval. Teva’s Advair competitor is non-substitutable, and the only true generics to get US FDA approval are from Mylan – also after a lengthy delay – and an authorised product from Prasco Laboratories. Any erosion to branded Advair’s US sales looks to be gradual.
|Advair and its generics|
|Company||US status||Note||Global 2019e sales|
|Glaxosmithkline||Available since 2001||Original brand||$2,232m|
|Teva||Airduo Respiclick approved Jan 2017||Not substitutable||$12m|
|Mylan||Wixela Inhub approved Jan 2019, after Mar 2017 CRL||Substitutable||$441m|
|Prasco Laboratories||Launched Feb 2019||Authorised generic||NA|
|Hikma/Vectura||CRL May 2017; upheld in Mar 2018||New study requested, Hikma responded Nov 2019||None|
|Sandoz (Novartis)||Discontinued after Feb 2018 CRL||Had been aiming to refile in 2019||None|
|Source: company releases & EvaluatePharma.|
Abbvie’s $63bn takeout of Allergan looks to have given Astrazeneca a retrospective $250m windfall. Last year the US group determined to divest the anti-IL-23 MAb brazikumab, which it was to acquire along with Allergan, on account of already owning the similarly-acting Skyrizi. Today a deal was hammered out, with brazikumab reverting to Astrazeneca, the company from which Allergan had licensed it for $250m up front three years ago. The development timeline is convoluted, the asset having been originated by Amgen before being licensed to Astra in 2012 along with four other MAbs, and Amgen retains a royalty interest, meaning that it will have been entitled to a share of the $250m Allergan had handed Astra in 2016. The main point, however, is that Astra does not appear to have had to pay anything to regain brazikumab; what is more, Allergan/Abbvie has agreed to fund part of the cost of developing the project for Crohn’s disease and ulcerative colitis. Interestingly, Abbvie never disclosed whether the brazikumab divestment had been prompted by regulators, though at a time of unusually stringent scrutiny even the hint of an antitrust issue is best avoided.
|The brazikumab timeline|
|Pre-2012||Brazikumab (then known as AMG 139) is originated by Amgen.|
|Apr 2012||Astrazeneca pays Amgen $50m up front under a joint development deal covering brazikumab (then coded MEDI2070), AMG 157, AMG 181, AMG 557 & brodalumab.|
|Apr 2015||Amgen suspends Astrazeneca co-development deal, retaining an option to resume participation later.|
|Nov 2016||Astrazeneca licenses brazikumab to Allergan for $250m up front.|
|Q2 2019||After buying Allergan for $63bn Abbvie determines to divest brazikumab and Zenpep, without disclosing whether this has been prompted by antitrust regulators.|
|Jan 2020||Astrazeneca reacquires brazikumab and a share of future development costs from Allergan/Abbvie for no apparent up-front consideration.|
New data from Grail’s vast basket trial, CCGA, add to the evidence that its liquid biopsy has reasonable accuracy, but do not show marked improvement in sensitivity compared with data presented at Asco last year. An exception could be hepatic disease; in May the sensitivity for stage I-III liver cancer, at a preset specificity of more than 99%, was 68%. The new data, to be presented at the Asco-GI meeting tomorrow, show a sensitivity for liver and intrahepatic bile duct cancers combined of 79% for stages I-III. How much of this improvement might be down to the inclusion of patients with intrahepatic bile duct cancers is, however, unclear. The researchers also examined the test’s ability to predict each cancer’s tissue of origin, and the results here are comparable to, or possibly worse than, earlier data. At Asco the assay correctly identified tissue of origin in 90% of liver cancers and 100% of pancreatic cancers; the rates at Asco-GI were 78% for liver/intrahepatic bile duct cancers and 92% for pancreas/gallbladder/extrahepatic bile duct tumours. Again, these are not exact comparisons, and the new data cut could represent a tougher population. The CCGA trial is scheduled to conclude next month, according to clinicaltrials.gov.
|Grail's Asco-GI data|
|Sensitivity||Predicted TOO accuracy|
|Cancer type||All||Stage I-III||Stage IV||All||Stage I-III||Stage IV|
extrahepatic bile duct
|Liver/intrahepatic bile duct||86%||79%||100%||78%||85%||70%|
|All GI cancers||82%||72%||96%||92%||92%||92%|
|All at >99% specificity. TOO=tissue of origin. Source: Asco-GI abstract #283.|
The latest results for Akcea and Ionis’s APOCIII-LRx in cardiovascular disease might not have been heavy on detail, but it was the absence of safety signals in the second-generation antisense project that excited investors, who pushed Akcea shares up 10%. The group now looks set to take the project, which Novartis declined to license, forward in the rare indication of familial chylomicronaemia syndrome, where it can conceivably progress on its own. As part of the multiple-arm, 114-patient study, APOCIII-LRx showed improvements in fasting triglycerides and increases in HDL cholesterol across all doses, with the greatest efficacy seen in the highest 50mg dose of APOCIII-LRx. More importantly, the most common adverse event was injection site reactions. Akcea, which is majority-owned by Ionis, has had a number of safety setbacks including a US complete response letter for Waylivera in 2018, and a black box warning for Tegsedi, so a clean bill of health for APOCIII-LRx was important in giving credence to arguments that its second-generation antisense products were safer. Before committing even more cash investors might want to pick through the details of APOCIII-LRx's seeming impressive efficacy and clean safety profile when the full results emerge.
While Car-T therapy has probably entered the public consciousness in the US the same cannot be said of Europe, but a 90-minute TV documentary about anticancer cell therapy, screened on the UK’s BBC2 last night, could help. “War in the Blood: A Cure for Cancer?” followed two adult ALL patients enrolled into two separate CD19-directed Car-T studies at University College London, and focused on the work of the UCL doctors Martin Pule (separately Autolus’s chief scientific officer), Emma Morris and Claire Roddie. The result was a programme that was accessible and moving, without being sentimental or glossing over scientific detail. Interestingly, one of the subjects was on a UCL study that uses donor-derived rather than autologous T cells – a concept previously tested by MD Anderson and the NCI – manufactured for administration in three repeat doses. It will not go unnoticed that sales of Car-T therapies in Europe significantly lag those in the US, though as direct-to-consumer advertising is illegal in the UK no products or companies were mentioned in yesterday’s documentary.
|Selected anti-CD19 Car-T therapy revenues|
|2024e sales ($m)|
|Source: EvaluatePharma US & Europe drug forecasts.|